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		Prestara^™ Clinical Trials

Genelabs has completed three Phase III double-blind, randomized, placebo controlled clinical trials of Prestara™ for women with systemic lupus erythematosus (SLE or lupus). The first of these, a Phase II/III trial, was completed in 1997, and evaluated Prestara's ability to reduce the glucocorticoid dose in steroid-dependent women with mild to moderate lupus. All 191 women with SLE in this trial previously required treatment with prednisone or other steroids. Patients in the trial received daily doses of 200 mg of Prestara, 100 mg of Prestara, or placebo for 7 to 9 months. The primary endpoint of this study was a sustained reduction in glucocorticoid dose to 7.5 mg per day or less, which are levels approximately equivalent to those normally produced by the adrenal glands. Although the primary endpoint was not achieved, among all patients enrolled in the study (intent-to-treat analysis), a trend in favor of Prestara was shown for the 200 mg dose over placebo (p=0.11). The effect was most evident in the 137 lupus patients with active disease, defined as those patients with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score greater than 2 at study entry. Among these patients, 51% of those who received daily doses of 200 mg of Prestara achieved the primary endpoint compared to 29% of those who received placebo (p=0.03). These data were published in the July 2002 issue of Arthritis and Rheumatism.

The second study, Study GL95-02, completed in 1999, evaluated Prestara's ability to improve or stabilize clinical outcome and disease symptoms in women with mild to moderate lupus. The 381 women with SLE, enrolled in 27 clinical sites participating in this trial, were randomized to receive either an oral dose of 200 mg of Prestara or placebo once a day for 12 months. All placebo and Prestara patients were allowed to continue taking their existing medications at fixed doses for the full course of this trial.

Among patients with active disease at baseline, Prestara-treated patients showed a 31% greater rate of response than the placebo group: 59% of Prestara patients responded to treatment compared to 45% of placebo patients. This increased rate of response, defined as improvement or stabilization in all four scoring instruments measured with no clinical deterioration, was statistically significant (p=0.017).

The scoring instruments utilized in this clinical trial included SLEDAI (SLE Disease Activity Index), SLAM (Systemic Lupus Activity Measure), Krupp Fatigue Severity Score, and Patient Global Assessment. The results of this study were published in the September 2004 issue of Arthritis and Rheumatism.

Loss of bone mineral density is a common manifestation of lupus and is also a significant side effect of glucocorticoids such as prednisone, one of the primary therapies for lupus. Because of this, nested within the second Phase III trial was a study conducted at eight of the investigator sites using dual x-ray absorptiometry (DXA) to assess bone mineral density in patients who had been taking glucocorticoids for at least 6 months prior to entering the trial.

An analysis of the results of this nested bone mineral density study, including all patients who had baseline and post-treatment bone mineral density measurements, showed that the group of patients receiving Prestara had increased bone mineral density, compared to a decrease in bone density for the group of patients receiving placebo. Between the Prestara and placebo treatment groups, the differences were statistically significant (measured by mean percentage change; 55 patients, p=0.003 at the lumbar spine and 53 patients, p=0.013 at the hip).

In its initial action on the Prestara NDA, the FDA issued a not-approvable letter. However, following further discussion and the submission of additional information including data and analysis regarding Prestara’s positive effect on bone mineral density, the FDA issued an approvable letter. In this letter, the FDA stated that approval of Prestara is contingent upon, among other things, the successful completion of an additional clinical trial to confirm the positive effect of Prestara on the bone mineral density of women with lupus who were receiving glucocorticoids. Separately, the FDA has stated that Study GL95-02 is a positive, adequate, and well controlled clinical trial with respect to its primary endpoint (see first chart).

After receiving the approvable letter, Genelabs conducted a third Phase III clinical trial, Study GL02-01, at 26 sites in the United States and Mexico. This trial was designed to confirm the positive effect of Prestara on bone mineral density that was previously noted. A total of 155 women with SLE were enrolled in this randomized, double-blind, placebo controlled study. The primary endpoint of this trial was bone mineral density at the lumbar spine and the treatment duration was 6 months with either 200 mg/day Prestara or placebo. All patients took at least 5 mg/day of glucocorticoids in addition to other standard SLE medications as needed.

In October 2004 Genelabs announced that Study GL02-01 did not meet its primary endpoint. An analysis of the data from this trial indicated that Prestara did not demonstrate a statistically significant difference between the bone mineral density of the group of patients taking Prestara and the group taking placebo, although a beneficial trend was observed.

All patients who completed Study GL02-01 were eligible to enroll in a one-year, open-label, follow-on study (Study GL03-01), in which patients received one of two different doses of Prestara. This study met its primary endpoint of maintaining the bone mineral density of the women receiving the therapeutic dose (200 mg/day) in the trial. In Study GL03-01, patients who received 200 mg of Prestara per day increased their BMD at the lumbar spine by approximately 0.9% during the 12 months they were enrolled in the study. Results of Study GL03-01 also demonstrated that patients who received a lower dose of Prestara, 100 mg per day, did not increase their BMD during the clinical trial, and in fact lost a measurable amount of bone mineral density at the lumbar spine over the 12-month period of the follow-on study.

In January 2006, Genelabs announced that the FDA had indicated that one additional, adequate, well-controlled phase III clinical trial would be necessary to support an indication for the treatment of the signs and symptoms of lupus. Separately, the FDA indicated that additional positive prospective phase III clinical trial data would be necessary before the FDA would consider reviewing an NDA for BMD in lupus. Based on this information, Genelabs plans to pursue an indication for treating the signs and symptoms of lupus and is in the process of designing a clinical trial protocol for an additional study, although the company does not believe that it will conduct the study on its own.

Adverse events related to taking Prestara (an adrenal hormone) observed in all clinical trials to date were generally mild and androgenic in nature, and include acne, facial hair growth, hormonal changes and a reduction in HDL cholesterol. Because the maximum exposure to Prestara in our trials is approximately two years, longer-term safety remains to be studied.